Methadone is commonly used in substitution
therapy of
heroin addicts; hence, its potential for modifying reactions to
opiates is of clinical importance. We compared the effects of repeated daily and every-other-day pre-exposure of rats to s.c.
morphine and
methadone on locomotor activity and CNS neuronal activation (as assessed by Fos immunohistochemistry) responses to s.c.
morphine challenge given 2 weeks after the completion of the pretreatment. The challenge revealed behavioral sensitization after daily
morphine pretreatment only. Dorsomedial striatum and basolateral amygdaloid nucleus showed robust
morphine-induced Fos
protein induction that was unaffected by the pretreatments tested. Centrolateral striatum, shell and core of the nucleus accumbens, paraventricular thalamic nucleus and some layers of motor and somatosensory cortices showed but negligible Fos
protein induction in drug-naive rats; this response was markedly enhanced by
morphine pretreatment only, which effect might be related to the emergence of
opiate addiction. Minor Fos responses to
morphine were also found in layers IV and VI of the somatosensory cortex and layer VI of the insular cortex of the drug-naïve rats; these responses were significantly enhanced both by
morphine and
methadone pretreatment. The similarity of
methadone and
morphine pretreatments' effects in the latter cortical regions might be relevant to the ability of
methadone to alleviate signs of abstinence syndrome and craving in
heroin addicts. In summary, this study revealed differing and relatively long-lasting effects of prolonged administration of
morphine and
methadone on the profile of behavioral and CNS neuronal activation responses to
morphine challenge in the rat.